Loss of 5-methylcytosine alters the biogenesis of vault-derived small RNAs to coordinate epidermal differentiation

Abdulrahim A. Sajini, Nila Roy Choudhury, Rebecca E. Wagner, Susanne Bornelöv, Tommaso Selmi, Christos Spanos, Sabine Dietmann, Juri Rappsilber, Gracjan Michlewski () and Michaela Frye ()
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Abdulrahim A. Sajini: University of Cambridge
Nila Roy Choudhury: University of Edinburgh
Rebecca E. Wagner: University of Cambridge
Susanne Bornelöv: Wellcome MRC Cambridge Stem Cell Institute
Tommaso Selmi: University of Cambridge
Christos Spanos: University of Edinburgh
Sabine Dietmann: Wellcome MRC Cambridge Stem Cell Institute
Juri Rappsilber: University of Edinburgh
Gracjan Michlewski: University of Edinburgh
Michaela Frye: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract The presence and absence of RNA modifications regulates RNA metabolism by modulating the binding of writer, reader, and eraser proteins. For 5-methylcytosine (m5C) however, it is largely unknown how it recruits or repels RNA-binding proteins. Here, we decipher the consequences of m5C deposition into the abundant non-coding vault RNA VTRNA1.1. Methylation of cytosine 69 in VTRNA1.1 occurs frequently in human cells, is exclusively mediated by NSUN2, and determines the processing of VTRNA1.1 into small-vault RNAs (svRNAs). We identify the serine/arginine rich splicing factor 2 (SRSF2) as a novel VTRNA1.1-binding protein that counteracts VTRNA1.1 processing by binding the non-methylated form with higher affinity. Both NSUN2 and SRSF2 orchestrate the production of distinct svRNAs. Finally, we discover a functional role of svRNAs in regulating the epidermal differentiation programme. Thus, our data reveal a direct role for m5C in the processing of VTRNA1.1 that involves SRSF2 and is crucial for efficient cellular differentiation.

Date: 2019
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DOI: 10.1038/s41467-019-10020-7

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